(S)-3-Hydroxybutyrolactone and a derivative, methyl (S)-3,4-O-isopropylidene-3,4-dihydroxybutanoate, are optically active starting materials in the preparation of [R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin), a new HMG-CoA reductase inhibitor (Nanninga, et al., Tetrahedron Lett., 1992;33:2279).
Chiral dihydroxybutyric acids and the corresponding esters, lactones, and derivatives have proven to be valuable chemical entities. In addition to useful intermediates in synthetic efforts towards natural products (Cf Benezra, et al., J. Org. Chem., 1985;50:1144; Hanessian, et al., Can. J. Chem., 1987;65:195; Ahn, et al., Tetrahedron Lett., 1992:507), a number of clinical applications have been disclosed. (S)-3-Hydroxybutyrolactone has been reported as a satiety agent (Okukado, et al., Bull. Chem. Soc. Jpn., 1988;61:2025) as well as a potentiating agent to neuroleptic drugs (Fuxe, et al., U.S. Pat. No. 4,138,484).
Clearly, there is a need for a simple and inexpensive method for the large scale preparation of (S)-3,4-dihydroxybutyric acid, (S)-3-hydroxybutyro-lactone, and derivatives of these chiral molecules. A large number of small scale complex syntheses have been reported demonstrating the value of these compounds.
Preparation of methyl (S)-3,4-O-isopropylidene-3,4-dihydroxybutanoate has been reported in the literature. It is prepared by reduction of dimethyl malate with borane-dimethyl sulfide complex/NaBH.sub.4 followed by acid catalyzed reaction with dimethoxypropane to yield the acetonide (Saito, et al., Chem. lett., 1984:1389; Tetrahedron, 1992;48:4067).
The acetonide has been prepared from isoascorbic acid via a multi-step sequence, but the yield was quite low due to the instability of an intermediate in the synthetic strategy (Tanaka, et al., Synthesis, 1987:570). The ethyl ester of the acetonide can be prepared from D-isoascorbic acid (Abushanab, et al., Synth. Comm., 1989;19:3077) via a similar multi-step route. An enzymatic resolution starting with racemic dimethyl malate has also been employed to produce the acetonide methyl ester on a small scale (Benezra, et al., J. Org. Chem., 1985;50:1144).
An additional reported procedure (Williams, et al., Tetrahedron Lett., 1988;29:5087) involves the direct oxidation of the corresponding acetonide aldehyde with alcoholic bromine to give the acetonide methyl ester in good yield.
Although there are a variety of routes to this acetonide ester, they all involve either expensive starting materials, difficult to handle reagents, or multi-step sequences.
There are a number of procedures in the literature for the preparation of (S)-3,4-dihydroxybutyric acid and the corresponding internal ester, (S)-3-hydroxybutyrolactone. The oxidation of water soluble carbohydrates to (S)-3,4-dihydroxybutyric acid and the corresponding lactone, (S)-3-hydroxybutyrolactone, has been reported (Hollingsworth, U.S. Pat. Nos. 5,292,939; 5,319,110; and 5,374,773). However, there is no discussion on how to isolate the product, (S)-3-hydroxybutyrolactone, except by chromatography. This hydroxylactone is very difficult to isolate from the reaction mixture due to the high water solubility of the molecule and the ease of decomposition/dehydration at the high temperatures required for purification by distillation. The preparation discussed in these patents is performed at high dilution, presumably due to the highly exothermic nature of the oxidation. In addition, this preparation does not provide the hydroxylactone ((S)-3-hydroxybutyrolactone) in the yields reported. Thus, this process is not readily amenable to large scale, economical preparations of (S)-3-hydroxybutyrolactone. Further, the above patents do not discuss the preparation of esters of (S)-3,4-O-isopropylidene-3,4-dihydroxybutyrate directly from carbohydrate oxidation reaction mixtures.
Preparation of (S)-3-hydroxybutyrolactone has been reported in a multi-step procedure starting with (S)-malic acid (Prestwich, et al., J. Org. Chem., 1981;46:4319). A slightly shorter route from either (S)-malic acid or aspartic acid has been reported (Larcheveque, et al., Synth. Commun., 1986;16:183) although the optical conversion of aspartic acid to malic acid was not 100% due to racemization of an intermediate. Esters of (S)-malic acid have also been utilized (Saito, et al., Chem. Lett., 1984:1389) using borane-dimethyl sulfide/sodium borohydride to prepare the dihydroxy ester followed by acid catalyzed cyclization to (S)-3-hydroxybutyrolactone.
A six-step procedure from D-isoascorbic acid has been reported (Tanaka, et al., Synthesis, 1987:570) but requires a diastereomeric separation and has been performed only on a small scale with purification by silica gel chromatography.
Oxidation and acid catalyzed cyclization of 6-(2,3-dihydroxypropyl)-1,3-dioxin-4-one has provided (s)-3-hydroxybutyrolactone in high optical purity but entails a six-step procedure (Sakaki, et al.; J. Chem. Soc., Chem. Commun., 1991:434).
Rabbit muscle aldolase catalyzed condensation of 3-hydroxy-4-oxobutanoate with dihydroxy acetone phosphate (DHAP) provided (S)-3-hydroxybutyrolactone with excellent optical purity on small scale (Whitesides, et al., J. Org. Chem., 1993;58:1887).
The preparation of (S)-3,4-dihydroxybutyric acid from (R)-3-chloro-1,2-propanediol via cyanation and hydrolysis of the dihydroxynitrile has been reported (Inoue, et al., U.S. Pat. No. 4,994,597). Oxidation of the corresponding hydroxyketone with perhexahydrobenzoic acid provides the 3-hydroxybutyrolactone (Cotarca, et al., International Published Patent Application, WO 94/29294) but no report of chiral purity is made.
The opposite enantiomer has been prepared by yeast reduction and cyclization of the appropriate ketoester (Seebach, et al., Synthesis, 1986:37). L-ascorbic acid (Luk, et al., Synthesis, 1988:226; Tanaka, et al., Synthesis, 1987:570) has been utilized to synthesis (R)-3-hydroxybutyrolactone via multi-step processes.
Optical resolution of racemic hydroxylactones using lipase has been reported (Miyazawa, et al., U.S. Pat. No. 5,084,392) but suffers due to only moderate enantiomeric excess and loss of the opposite enantiomer. Long reaction times are also reported with this procedure. Carbonylation of glycidol using a cobalt catalyst has been employed but requires high pressures to effect carbonylation and produces a significant quantity of unsaturated ester. The use of a chiral glycidol in the process to provide optically active lactones is not addressed (Brima, et al., U.S. Pat. No. 4,968,817). Acid catalyzed deprotection and subsequent lactonization of methyl (R)-3,4-O-isopropylidene-3,4-dihydroxybutanoate has been employed to prepare (R)-3-hydroxybutyrolactone (Luk, et al., Synthesis, 1988:226; Tanaka, et al., Synthesis, 1987:570). The corresponding cyclohexylidene protected ester of methyl (S)-3,4-dihydroxybutyrate has been deprotected and lactonized with dilute aqueous acid to provide (S)-3-hydroxybutyrolactone (Tanaka, et al., Synthesis, 1987:570).
Direct formation of the acetonide methyl ester from a similar hydroxylactone has been reported in the literature, but this procedure employs a purified lactone as the starting material (Larcheveque, et al., Tetrahedron, 1987;43:2303).
The object of the present invention is an inexpensive, scalable, direct route to esters of (S)-3,4-O-isopropylidene-3,4-dihydroxybutyric acid and (S)-3-hydroxybutyrolactone from a carbohydrate source.